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Export of Misfolded Proteins out of the ER01:32

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After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
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ER is the primary site for the maturation and folding of soluble and transmembrane secretory proteins. The calnexin cycle is a specific chaperone system that folds and assesses the confirmation of N-glycosylated proteins before they can exit the ER lumen. The primary players of this quality check pipeline are the lectins, ER-resident chaperones, and a glucosyl transferase enzyme. In case the calnexin system in the lumen fails to salvage a misfolded protein, it is transported to the cytoplasm...
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Cycloheximide Chase Analysis of Protein Degradation in Saccharomyces cerevisiae
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Hexosamine pathway and (ER) protein quality control.

Martin S Denzel1, Adam Antebi2

  • 1Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, 50931 Cologne, Germany.

Current Opinion in Cell Biology
|December 3, 2014
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Summary

The hexosamine pathway (HP) regulates protein quality control and aging. Activating the HP, through compounds like glucosamine, enhances stress resistance and extends lifespan by combating age-related proteotoxicity.

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Area of Science:

  • Biochemistry
  • Cell Biology
  • Gerontology

Background:

  • Aminosugars from the hexosamine pathway (HP) are crucial for protein glycosylation, impacting protein maturation and cellular signaling.
  • Emerging research highlights the HP's involvement in protein quality control and the aging process.
  • The HP's key enzyme, glutamine-fructose 6 phosphate aminotransferase (GFAT-1), is implicated in cellular stress responses.

Purpose of the Study:

  • To explore the role of hexosamine pathway activation in cellular stress resistance and the suppression of age-related proteotoxicity.
  • To discuss the connection between HP activation, protein quality control, and extended lifespan.
  • To review how GFAT-1 activation by cellular stress contributes to cytoprotective mechanisms.

Main Methods:

  • Investigating the effects of UDP-N-acetylglucosamine elevation in Caenorhabditis elegans on resistance to toxic proteins and lifespan.
  • Examining GFAT-1 activation as a response to cardiac stress in mice.
  • Analyzing the impact of glucosamine supplementation on the life expectancy of aged mice.

Main Results:

  • Elevating UDP-N-acetylglucosamine in C. elegans conferred resistance to toxic proteins and extended lifespan.
  • Cardiac stress in mice led to GFAT-1 activation, initiating a cytoprotective response.
  • Glucosamine feeding extended the lifespan of aged mice.

Conclusions:

  • Hexosamine pathway activation is a key mechanism for enhancing cellular stress resistance and combating age-related proteotoxicity.
  • The HP plays a significant role in regulating lifespan and protecting against protein aggregation.
  • Targeting the HP offers a potential strategy for interventions aimed at promoting healthy aging.